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首页> 美国卫生研究院文献>other >Inflammation-induced dysfunction of the low-density lipoprotein receptor-related protein-1 at the blood-brain barrier: Protection by the antioxidant N-acetylcysteine
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Inflammation-induced dysfunction of the low-density lipoprotein receptor-related protein-1 at the blood-brain barrier: Protection by the antioxidant N-acetylcysteine

机译：炎症诱导的低密度脂蛋白受体相关蛋白-1在血脑屏障下的功能障碍：通过抗氧化剂N-乙酰半胱氨酸的保护

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Impairment in two blood-brain barrier (BBB) efflux transporters, p-glycoprotein (Pgp) and low-density lipoprotein receptor-related protein-1 (LRP-1) are thought to contribute to the progression of Alzheimer’s disease (AD) by resulting in the brain accumulation of their substrate amyloid beta peptide (Aβ). The initial cause of impaired efflux, however, is unknown. We have shown that induction of systemic inflammation by intraperitoneal administration of lipopolysaccharide impairs the efflux of Aβ from the brain, suggesting that systemic inflammation could be one such initiator. In this study, we determined whether pre-administration of the antioxidant N-aceytlcysteine (Nac) has a protective effect against LPS-induced Aβ transporter dysfunction. Our findings were that Nac protected against LPS-induced Aβ transport dysfunction at the BBB through an LRP-1-dependent and Pgp-independent mechanism. This was associated with Nac exerting antioxidant effects in the periphery but not the brain, despite an increased rate of entry of Nac into the brain following LPS. We also found that Nac pre-administration resulted in lower blood levels of the cytokines and chemokines interferon-γ, interleukin-10, CCL2, CCL4, and CL5, but only lowered CCL4 in the cerebral cortex and hippocampus. Finally, we observed that hippocampal cytokine responses to LPS were decreased compared to cortex. These findings demonstrate a novel mechanism by which antioxidants prevent Aβ accumulation in the brain caused by inflammation, and therefore protect against AD.
机译：据认为，两种血脑屏障（BBB）外向转运蛋白，p-糖蛋白（Pgp）和低密度脂蛋白受体相关蛋白-1（LRP-1）的受损通过以下原因促进了阿尔茨海默氏病（AD）的发展：在大脑中积累了其底​​物淀粉样β肽（Aβ）。然而，外排受损的最初原因尚不清楚。我们已经表明，通过腹膜内给予脂多糖诱导的全身性炎症会损害大脑中Aβ的流出，这表明全身性炎症可能是一种此类引发剂。在这项研究中，我们确定抗氧化剂N-乙酰半胱氨酸（Nac）的预先给药是否对LPS诱导的Aβ转运蛋白功能障碍具有保护作用。我们的发现是Nac通过LRP-1依赖性和Pgp依赖性机制保护了BPS免受LPS诱导的Aβ转运功能障碍。尽管Lac引起Nac进入大脑的比率增加，但这与Nac在外周而不是大脑发挥抗氧化作用有关。我们还发现，预先服用Nac可以降低血液中的细胞因子和趋化因子干扰素-γ，白介素10，CCL2，CCL4和CL5的血药水平，但只会降低大脑皮层和海马中的CCL4。最后，我们观察到，与皮质相比，海马对LPS的细胞因子反应降低。这些发现证明了一种新的机制，抗氧化剂可通过该机制防止炎症引起的大脑Aβ积累，从而预防AD。

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